When to begin treatment for patients with multiple sclerosis (MS) has become a contentious subject. Neurologists and patients are confronted with a situation where drug therapy for this progressive disease can sometimes be as burdensome—physically, emotionally, and financially—as the disease itself. Groundbreaking immunotherapies have on the one hand offered hitherto untreatable patients hope for slowing the disease’s progression and, on the other, saddled them with a lifelong regimen of daily injections, significant side effects, and a high cost for treatment.

Now, the results of a major study dispute the need to treat most patients with MS. In a population-based cohort study that followed patients first examined 10 years ago, investigators at the Mayo Clinic in Rochester, Minnesota, found that less than one third of patients had progressed to a more disabling state of MS—such as needing a cane or a wheelchair—while the majority of patients had remained stable or progressed minimally. In fact, two thirds of patients who had a low disability score in 1991 were found to have the same or a comparable score 10 years later. Overall, about 25% of the patients continued to have a benign course, the investigators reported in the January 13 Neurology.

Such results represent good news for patients and “totally unexpected” news for clinicians, said principal investigator Moses Rodriguez, MD. He began working on the study with the same assumption about MS that he felt everyone else in the field had—that of a relatively progressive disease in which most patients measured 10 years later would be doing worse. But that was not at all what he and his colleagues found, and much of the evidence pointed in the opposite direction: For example, of the 25% of patients who had almost completely benign disease, practically nothing was happening to them, Dr. Rodriguez observed. “They clearly have MS; they have lots of lesions on MRI scans,” he said. “But clinically, they weren’t seeing doctors, they were on no medicine, they had no concerns, they were living a perfectly normal life.”

Although about 30% of the patients did worsen significantly, the entire cohort progressed only by a slight amount: approximately a 1-point drop on the Expanded Disability Status Scale (EDSS), said Dr. Rodriguez, a Professor in the Departments of Neurology and Immunology at Mayo Clinic College of Medicine. Without wishing to minimize the disease severity faced by the subgroup of patients who will progress more rapidly, Dr. Rodriguez hailed these results as offering real hope for MS patients, especially those who are newly diagnosed.

“The good news is that if you’re diagnosed with MS, it doesn’t necessarily carry a bad prognosis,” he said. “For a large number of patients, it’s a relatively good prognosis. And you begin to question very seriously this whole need to treat early.

“Maybe for some patients watchful waiting is a good approach. Because obviously the last thing you want to do is take somebody who is going to have a benign course and treat him or her with 25 years of ß-interferon that costs $10,000 a year, causes side effects, and requires the patient to inject him- or herself every day, as opposed to waiting to see what happens.”

UNIQUE CIRCUMSTANCES AND AN EXCEPTIONAL PATIENT POPULATION

The Mayo Clinic study is unique in several respects and, in Dr. Rodriguez’s view, unprecedented—at least with respect to MS studies. For the first time, researchers were able to examine the same patients (or their medical records) from a geographic cohort in Olmsted County, Minnesota, that they had studied 10 years earlier. Enabling this precedent is the Mayo Clinic’s singular position as the only major health care provider (along with one small community hospital) in Olmsted County: sooner or later, virtually everyone in the county gets treated at the Mayo Clinic, Dr. Rodriguez said.

In addition, the Mayo Clinic’s long-established role as one of the world’s premier research institutions can provide resident investigators with a wealth of historical data. Researchers at the clinic have been studying MS in Olmsted County since 1905, culling incidence and prevalence data that can prove very useful to a population-based cohort study such as the one conducted by Dr. Rodriguez and colleagues.

When he came to the Mayo Clinic about 25 years ago, Dr. Rodriguez was interested in the issue of what happens to MS patients in a community setting. At that time, there had been few population-based studies of MS, and most studies were based on data obtained at MS clinics, which tend to see patients who are not doing well, Dr. Rodriguez explained.

“So you have a tendency to think about MS in a certain way, and that’s been the impression that has been left with a lot of clinicians, since those are the kind of patients they are seeing,” he said. “I wanted to do a true prevalence cohort study, where I would try to see and examine literally every single [MS] patient in the community irrespective of how they were doing.”

That research resulted in a study of impairment, disability, and handicap among 162 Olmsted County residents with MS that was published in 1994 and laid the groundwork for the follow-up study conducted 10 years later. Remarkably, Dr. Rodriguez and his colleagues were able to follow all but one of the original 162 patients.

Dr. Rodriguez remains “absolutely convinced” that the original 1991 cohort of 162 persons represented just about everyone in the county who had MS. With a population just under 100,000, Olmsted County would already have the highest prevalence rate of MS in the country if Dr. Rodriguez’s estimation is correct, so it may be reasonable for him to conclude that he and his colleagues found everyone with MS.

DISCOVERING THE TRUE NATURAL HISTORY OF MS

There is one other aspect to this study that supports Dr. Rodriguez’s view that it is one of a kind: The great majority of patients (about 85%) were not on treatment. “As you know, MS is now being treated by a lot of different therapies, and the whole approach is to treat patients early,” he said. “So this [kind of study] will never happen again because, basically, we were able to do the study before the big surge of people being put on treatment occurred.”

In essence, the Mayo Clinic study represents as close to a true natural history study as any investigators are likely to get. And the results of the study suggest that the natural history of MS for many patients can remain benign for years—making treatment unwarranted.

“Our study shows there is a very clear indication that if you are doing well for a period of five years and you have no disability, your chances of having severe disability 10, 20, or even 30 years later are less than 10%,” Dr. Rodriguez said. “The first five years of the disease course are a very good predictor of what will happen to you long term.”

Such patients, who have an EDSS score of less than 2 and who represented about one quarter of the population in the Mayo Clinic study, have become an extremely important subgroup with respect to the etiology of MS, Dr. Rodriguez maintained. “Because if we can figure out why those patients remain so well in spite of having what looks like really bad disease on the MRI scan, it tells us something very important,” he said.

Dr. Rodriguez and his colleagues are following this subgroup from Olmsted County closely and have collected DNA from every single patient, plus family members, and have also collected DNA from an ethnically matched control group in the community—with the aim of investigating the genetic basis of why some patients do well and others do not.

CLOSE OBSERVATION NEEDED

In the meantime, Dr. Rodriguez remains concerned about the tendency of many clinicians to put patients who present with MS on immunomodulatory therapy—in the absence of even mild symptoms. He ticked off the main side effects: flu-like symptoms, nausea and vomiting, a heightened risk of liver problems, and injection reactions.

“You have to inject yourself every day,” he said, “and once you start treatment you have to be treated forever.… If you happen to be a benign patient and you get put on one of these drugs, you go to see your doctor and the doctor’s going to say, ‘You’re doing great. Guess what? That drug is doing marvelously well. There’s no way we’re going to take you off of this drug, right?’—when, in reality, you would have done well anyway.”

The last thing clinicians want to do is to take a patient who has a benign course and treat with a drug that could potentially make him or her worse, Dr. Rodriguez emphasized. Instead, he recommends a period of observation before drug treatment is initiated.

“Our study strongly supports the idea that close observation is warranted—and by close observation I mean seeing patients regularly and monitoring them and, obviously, if they start becoming disabled, beginning treatment at that point,” he concluded. “But if the patient remains clinically normal—even though he or she has MRI findings of MS—I would be very hesitant to treat.”

NR

—Fred Balzac

Suggested Reading
Pittock SJ, Mayr WT, McClelland RL, et al. Change in MS-related disability in a population-based cohort: a 10-year follow-up study. Neurology. 2004;62:51-59.
Rodriguez M, Siva A, Ward J, et al. Impairment, disability, and handicap in multiple sclerosis: a population-based study in Olmsted County, Minnesota. Neurology. 1994;44:28-33.

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